Inflammation and pain affect large and ever-increasing patient populations. Narcotics, corticosteroids, and NSAIDs are effective, but they are associated with tremendous adverse effects which now account for thousands of deaths each year. The long-term objective of this proposal is to develop a CRF receptor antagonist as an analgesic andanti-inflammatory agent with a novel mechanism of action, with equivalent anti-inflammatory and analgesic effects and an improved side-effect profile compared to currently available treatments. In preliminary experiments we have shown that tissue-resident mast cells in inflamed tissues have CRF receptors, and that CRF antagonists attenuate activation of these mast cells and produce robust analgesic effects. In Phase I, using rodent models of acute and chronic inflammation, we propose to determine if the analgesic effects of CRF antagonists can be attributed entirely to peripheral CRF-R1 receptors, if the analgesic and anti-inflammatory effects of CRF antagonists are detectable in chronic as well as acute inflammation, and if CRF antagonists are effective and have a low side-effect profile even after chronic administration. Phase II will focus on the medicinal chemistry, in vitro and in vivo biology needed to produce a small molecule CRF antagonist with optimal characteristics for the treatment of inflammatory disorders. PROPOSED COMMERCIAL APPLICATION: This research, if successful, will result in small molecule antagonists of the corticotropin releasing factor receptor with maximum potency for anti-inflammatory and analgesic effects. Orally active forms of a small molecule CRF receptor would provide a novel therapeutic strategy for indications of acute and chronic inflammation and inflamatory pain.